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Angus John Clarke - One of the best experts on this subject based on the ideXlab platform.
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reliability of prenatal detection of x linked Hypohidrotic Ectodermal Dysplasia by tooth germ sonography
Prenatal Diagnosis, 2019Co-Authors: Johanna Hammersen, Sigrun Wohlfart, T W Goecke, A Koninger, H Stepan, Ralph Gallinat, Susan Morris, Katharina Bucher, Angus John ClarkeAbstract:Objective In X‐linked Hypohidrotic Ectodermal Dysplasia (XLHED), dysfunction of ectodysplasin A1 (EDA1) due to EDA mutations results in malformation of hair, teeth, and sweat glands. Hypohidrosis, which can cause life‐threatening hyperthermia, is amenable to intrauterine therapy with recombinant EDA1. This study aimed at evaluating tooth germ sonography as a noninvasive means to identify affected fetuses in pregnant carrier women. Methods Sonography, performed at 10 study sites between gestational weeks 18 and 28, led to the diagnosis of XLHED if fewer than six tooth germs were detected in mandible or maxilla. The assessment was verified postnatally by EDA sequencing and/or clinical findings. Estimated fetal weights and postnatal weight gain of boys with XLHED were assessed using appropriate growth charts. Results In 19 of 38 sonographic examinations (23 male and 13 female fetuses), XLHED was detected prenatally. The prenatal diagnosis proved to be correct in 37 cases; one affected male fetus was missed. Specificity and positive predictive value were both 100%. Tooth counts obtained by clinical examination corresponded well with findings on panoramic radiographs. We observed no weight deficits of subjects with XLHED in utero but occasionally during infancy. Conclusion Tooth germ sonography is highly specific and reliable in detecting XLHED prenatally.
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clinical and radiographic dental findings in x linked Hypohidrotic Ectodermal Dysplasia
Journal of Medical Genetics, 1991Co-Authors: P J Crawford, Michael J Aldred, Angus John ClarkeAbstract:X linked Hypohidrotic Ectodermal Dysplasia was studied in the dentition of both affected males and carrier females. Hypodontia was more severe in males than females and there were differences in the pattern of tooth absence between the sexes. Abnormal crown form, with the maximum diameter of the teeth being apically displaced, was noted particularly in the anterior teeth. Taurodontism was commonly seen radiographically.
Holm Schneider - One of the best experts on this subject based on the ideXlab platform.
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variants of the ectodysplasin a1 receptor gene underlying homozygous cases of autosomal recessive Hypohidrotic Ectodermal Dysplasia
Clinical Genetics, 2019Co-Authors: Sigrun Wohlfart, Holm SchneiderAbstract:Hypohidrotic Ectodermal Dysplasia (HED) is a rare genetic condition resulting from defective development of Ectodermal derivatives, such as hair, teeth, and sweat glands. Autosomal recessive (AR) forms of HED may be caused by pathogenic variants of the ectodysplasin A1 receptor (EDAR) gene that encodes a receptor involved in the NF-κB signaling pathway. Here, we describe three cases of AR-HED in families of Turkish, Austrian, and German-American origin (with or without known consanguinity). In these cases, two out-of-frame deletions and a pathogenic missense variant of EDAR were found to be disease-causing due to reduced availability of the respective messenger RNA or impaired interaction of the encoded protein with its binding partner leading to diminished signal transduction. The same missense variant, c.1258C>T (p.Arg420Trp), has actually been reported to be restricted to the Icelandic population and to be associated with non-syndromic tooth agenesis but not HED. As our patient has no known relationship to Icelandic individuals and displays a rather severe HED phenotype, we suggest that EDAR-Arg420Trp is a more widespread variant, possibly with variable clinical expressivity.
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Hypohidrotic Ectodermal Dysplasia breastfeeding complications due to impaired breast development
Geburtshilfe Und Frauenheilkunde, 2017Co-Authors: Mandy Wahlbuhlbecker, F Faschingbauer, Matthias W Beckmann, Holm SchneiderAbstract:Background X-linked Hypohidrotic Ectodermal Dysplasia (XLHED), the most common form of Ectodermal Dysplasia, is caused by mutations in the gene EDA. While only affected men develop the full-blown clinical picture, females who are heterozygous for an EDA mutation often also show symptoms such as hypodontia, hypotrichosis and hypohidrosis. These women may also suffer from malformations of the mammary gland which represent not just a cosmetic problem but can limit their breastfeeding capability. This paper summarizes the findings of the first systematic study on the impact of Hypohidrotic Ectodermal Dysplasia on breastfeeding. Patients Thirty-eight adult female members of the German-Swiss-Austrian Ectodermal Dysplasia patient support group participated in a structured interview; most of them also agreed to a photodocumentation of their mammary region. Thirty-one women carried mutations in EDA (Group A) and seven were affected by other forms of Hypohidrotic Ectodermal Dysplasia (Group B). Results 39 % of the women of Group A reported that their breasts were of different size or entirely absent on one side. In Group B, 86 % of the women reported differently sized or even absent breasts; two of these women lacked both breasts entirely. Most women described their nipples as exceptionally flat. 10 % of the women of Group A had more than two nipples. The high percentage of deviations from the norm was confirmed in the photodocumentation. Both groups had few or no sebaceous glands of Montgomery in the areolar region. Around 80 % of interviewed women had children and had attempted to breastfeed their first child. 67 % of the mothers in Group A had had difficulty in breastfeeding their infants and generally attributed this difficulty to their flat nipples. All of the mothers in Group B reported difficulties in breastfeeding; 60 % had not been able to breastfeed their first child. Conclusion Mothers with Hypohidrotic Ectodermal Dysplasia very often have difficulty in breastfeeding because of their impaired breast development. This causal relationship needs to be taken into account in lactation counseling.
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a novel missense mutation in the gene edaradd associated with an unusual phenotype of Hypohidrotic Ectodermal Dysplasia
American Journal of Medical Genetics Part A, 2016Co-Authors: Sigrun Wohlfart, A Smahi, Stephan Soder, Holm SchneiderAbstract:Hypohidrotic Ectodermal Dysplasia (HED) is a rare disorder characterized by deficient development of structures derived from the ectoderm including hair, nails, eccrine glands, and teeth. HED forms that are caused by mutations in the genes EDA, EDAR, or EDARADD may show almost identical phenotypes, explained by a common signaling pathway. Proper interaction of the proteins encoded by these three genes is important for the activation of the NF-κB signaling pathway and subsequent transcription of the target genes. Mutations in the gene EDARADD are most rarely implicated in HED. Here we describe a novel missense mutation, c.367G>A (p.Asp123Asn), in this gene which did not appear to influence the interaction between EDAR and EDARADD proteins, but led to an impaired ability to activate NF-κB signaling. Female members of the affected family showed either unilateral or bilateral amazia. In addition, an affected girl developed bilateral ovarian teratomas, possibly associated with her genetic condition.
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prenatal therapy in developmental disorders drug targeting via intra amniotic injection to treat x linked Hypohidrotic Ectodermal Dysplasia
Journal of Investigative Dermatology, 2014Co-Authors: Katharina Hermes, Kenneth M Huttner, Pascal Schneider, Peter Krieg, Anhthu Dang, Holm SchneiderAbstract:Background Disorders that irremediably affect fetuses make early stage therapies desirable. X-linked Hypohidrotic Ectodermal Dysplasia (XLHED), the most common inherited disorder of ectoderm development affecting the skin and its appendages, glands, and teeth, is caused by a lack of the signaling molecule ectodysplasin A1 (EDA1). In the Tabby XLHED mouse model, repeated intravenous administration of EDA1 to pregnant mice has been shown to correct the developmental abnormalities in the offspring. Maternal drug administration, however, exposes mothers to potential drug toxicity and is limited by the variability in transplacental drug delivery. Alternative approaches to fetal treatment should entail low risk drug delivery with reproducible pharmacokinetics. We hypothesized that a single injection of an EDA1 replacement molecule into the amniotic fluid could allow sustained drug exposure at levels sufficient for correction of XLHED.
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genotype phenotype correlation in boys with x linked Hypohidrotic Ectodermal Dysplasia
American Journal of Medical Genetics Part A, 2014Co-Authors: Kristin Burger, Sigrun Wohlfart, Kenneth M Huttner, Ramsey Johnson, Anne-theres Schneider, Franklin Kiesewetter, Holm SchneiderAbstract:X-linked Hypohidrotic Ectodermal Dysplasia (XLHED), the most frequent form of Ectodermal Dysplasia, is a genetic disorder of ectoderm development characterized by malformation of multiple Ectodermal structures such as skin, hair, sweat and sebaceous glands, and teeth. The disease is caused by a broad spectrum of mutations in the gene EDA. Although XLHED symptoms show inter-familial and intra-familial variability, genotype–phenotype correlation has been demonstrated with respect to sweat gland function. In this study, we investigated to which extent the EDA genotype correlates with the severity of XLHED-related skin and hair signs. Nineteen male children with XLHED (age range 3–14 years) and seven controls (aged 6–14 years) were examined by confocal microscopy of the skin, quantification of pilocarpine-induced sweating, semi-quantitative evaluation of full facial photographs with respect to XLHED-related skin issues, and phototrichogram analysis. All eight boys with known hypomorphic EDA mutations were able to produce at least some sweat and showed less severe cutaneous signs of XLHED than the anhidrotic XLHED patients (e.g., perioral and periorbital eczema or hyperpigmentation, regional hyperkeratosis, characteristic wrinkles under the eyes). As expected, individuals with XLHED had significantly less and thinner hair than healthy controls. However, there were also significant differences in hair number, diameter, and other hair characteristics between the group with hypomorphic EDA mutations and the anhidrotic patients. In summary, this study indicated a remarkable genotype–phenotype correlation of skin and hair findings in prepubescent males with XLHED. © 2014 Wiley Periodicals, Inc.
S. Mundlos - One of the best experts on this subject based on the ideXlab platform.
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Identification of a Novel Missense Mutation in EDAR Causing Autosomal Recessive Hypohidrotic Ectodermal Dysplasia with Bilateral Amastia and Palmoplantar Hyperkeratosis
The British journal of dermatology, 2013Co-Authors: Alireza Haghighi, Pooneh Nikuei, Hamidreza Haghighi-kakhki, Nasrollah Saleh-gohari, S. Baghestani, P.m. Krawitz, Jochen Hecht, S. MundlosAbstract:Ectodermal Dysplasias (EDs) are a large group of heritable complex conditions with more than ٢٠٠ members and common clinical characteristics of anomalies of the hair, teeth, nails, and sweat glands with or without involvement of other organs (١) . Anhidrotic or Hypohidrotic Ectodermal Dysplasia (EDA/ HED) is the most common form of EDs which is characterized by the clinical triad of hypotrichosis (sparse hair), abnormal or missing teeth (anodontia or hypodontia), and deficient sweating (hypohidrosis or anhidrosis) (٢) . Different modes of inheritance have been described for HED. X-linked HED (OMIM: ٣٠٥١٠٠) is caused by mutations in ectodysplasin A gene (EDA١), whereas mutations in the EDA receptor (EDAR) and EDAR-associated death domain (EDARADD) genes result in autosomal dominant (OMIM:١٢٩٤٩٠) and autosomal recessive (OMIM: ٢٢٤٩٠٠) forms (٣) .
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whole exome sequencing identifies a novel missense mutation in edar causing autosomal recessive Hypohidrotic Ectodermal Dysplasia with bilateral amastia and palmoplantar hyperkeratosis
British Journal of Dermatology, 2013Co-Authors: Alireza Haghighi, Pooneh Nikuei, S. Baghestani, P.m. Krawitz, Jochen Hecht, S. Mundlos, Hamidreza Haghighikakhki, Nasrollah SalehgohariAbstract:Ectodermal Dysplasias (EDs) are a large group of heritable complex conditions with more than ٢٠٠ members and common clinical characteristics of anomalies of the hair, teeth, nails, and sweat glands with or without involvement of other organs (١) . Anhidrotic or Hypohidrotic Ectodermal Dysplasia (EDA/ HED) is the most common form of EDs which is characterized by the clinical triad of hypotrichosis (sparse hair), abnormal or missing teeth (anodontia or hypodontia), and deficient sweating (hypohidrosis or anhidrosis) (٢) . Different modes of inheritance have been described for HED. X-linked HED (OMIM: ٣٠٥١٠٠) is caused by mutations in ectodysplasin A gene (EDA١), whereas mutations in the EDA receptor (EDAR) and EDAR-associated death domain (EDARADD) genes result in autosomal dominant (OMIM:١٢٩٤٩٠) and autosomal recessive (OMIM: ٢٢٤٩٠٠) forms (٣) .
Sigrun Wohlfart - One of the best experts on this subject based on the ideXlab platform.
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reliability of prenatal detection of x linked Hypohidrotic Ectodermal Dysplasia by tooth germ sonography
Prenatal Diagnosis, 2019Co-Authors: Johanna Hammersen, Sigrun Wohlfart, T W Goecke, A Koninger, H Stepan, Ralph Gallinat, Susan Morris, Katharina Bucher, Angus John ClarkeAbstract:Objective In X‐linked Hypohidrotic Ectodermal Dysplasia (XLHED), dysfunction of ectodysplasin A1 (EDA1) due to EDA mutations results in malformation of hair, teeth, and sweat glands. Hypohidrosis, which can cause life‐threatening hyperthermia, is amenable to intrauterine therapy with recombinant EDA1. This study aimed at evaluating tooth germ sonography as a noninvasive means to identify affected fetuses in pregnant carrier women. Methods Sonography, performed at 10 study sites between gestational weeks 18 and 28, led to the diagnosis of XLHED if fewer than six tooth germs were detected in mandible or maxilla. The assessment was verified postnatally by EDA sequencing and/or clinical findings. Estimated fetal weights and postnatal weight gain of boys with XLHED were assessed using appropriate growth charts. Results In 19 of 38 sonographic examinations (23 male and 13 female fetuses), XLHED was detected prenatally. The prenatal diagnosis proved to be correct in 37 cases; one affected male fetus was missed. Specificity and positive predictive value were both 100%. Tooth counts obtained by clinical examination corresponded well with findings on panoramic radiographs. We observed no weight deficits of subjects with XLHED in utero but occasionally during infancy. Conclusion Tooth germ sonography is highly specific and reliable in detecting XLHED prenatally.
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variants of the ectodysplasin a1 receptor gene underlying homozygous cases of autosomal recessive Hypohidrotic Ectodermal Dysplasia
Clinical Genetics, 2019Co-Authors: Sigrun Wohlfart, Holm SchneiderAbstract:Hypohidrotic Ectodermal Dysplasia (HED) is a rare genetic condition resulting from defective development of Ectodermal derivatives, such as hair, teeth, and sweat glands. Autosomal recessive (AR) forms of HED may be caused by pathogenic variants of the ectodysplasin A1 receptor (EDAR) gene that encodes a receptor involved in the NF-κB signaling pathway. Here, we describe three cases of AR-HED in families of Turkish, Austrian, and German-American origin (with or without known consanguinity). In these cases, two out-of-frame deletions and a pathogenic missense variant of EDAR were found to be disease-causing due to reduced availability of the respective messenger RNA or impaired interaction of the encoded protein with its binding partner leading to diminished signal transduction. The same missense variant, c.1258C>T (p.Arg420Trp), has actually been reported to be restricted to the Icelandic population and to be associated with non-syndromic tooth agenesis but not HED. As our patient has no known relationship to Icelandic individuals and displays a rather severe HED phenotype, we suggest that EDAR-Arg420Trp is a more widespread variant, possibly with variable clinical expressivity.
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a novel missense mutation in the gene edaradd associated with an unusual phenotype of Hypohidrotic Ectodermal Dysplasia
American Journal of Medical Genetics Part A, 2016Co-Authors: Sigrun Wohlfart, A Smahi, Stephan Soder, Holm SchneiderAbstract:Hypohidrotic Ectodermal Dysplasia (HED) is a rare disorder characterized by deficient development of structures derived from the ectoderm including hair, nails, eccrine glands, and teeth. HED forms that are caused by mutations in the genes EDA, EDAR, or EDARADD may show almost identical phenotypes, explained by a common signaling pathway. Proper interaction of the proteins encoded by these three genes is important for the activation of the NF-κB signaling pathway and subsequent transcription of the target genes. Mutations in the gene EDARADD are most rarely implicated in HED. Here we describe a novel missense mutation, c.367G>A (p.Asp123Asn), in this gene which did not appear to influence the interaction between EDAR and EDARADD proteins, but led to an impaired ability to activate NF-κB signaling. Female members of the affected family showed either unilateral or bilateral amazia. In addition, an affected girl developed bilateral ovarian teratomas, possibly associated with her genetic condition.
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genotype phenotype correlation in boys with x linked Hypohidrotic Ectodermal Dysplasia
American Journal of Medical Genetics Part A, 2014Co-Authors: Kristin Burger, Sigrun Wohlfart, Kenneth M Huttner, Ramsey Johnson, Anne-theres Schneider, Franklin Kiesewetter, Holm SchneiderAbstract:X-linked Hypohidrotic Ectodermal Dysplasia (XLHED), the most frequent form of Ectodermal Dysplasia, is a genetic disorder of ectoderm development characterized by malformation of multiple Ectodermal structures such as skin, hair, sweat and sebaceous glands, and teeth. The disease is caused by a broad spectrum of mutations in the gene EDA. Although XLHED symptoms show inter-familial and intra-familial variability, genotype–phenotype correlation has been demonstrated with respect to sweat gland function. In this study, we investigated to which extent the EDA genotype correlates with the severity of XLHED-related skin and hair signs. Nineteen male children with XLHED (age range 3–14 years) and seven controls (aged 6–14 years) were examined by confocal microscopy of the skin, quantification of pilocarpine-induced sweating, semi-quantitative evaluation of full facial photographs with respect to XLHED-related skin issues, and phototrichogram analysis. All eight boys with known hypomorphic EDA mutations were able to produce at least some sweat and showed less severe cutaneous signs of XLHED than the anhidrotic XLHED patients (e.g., perioral and periorbital eczema or hyperpigmentation, regional hyperkeratosis, characteristic wrinkles under the eyes). As expected, individuals with XLHED had significantly less and thinner hair than healthy controls. However, there were also significant differences in hair number, diameter, and other hair characteristics between the group with hypomorphic EDA mutations and the anhidrotic patients. In summary, this study indicated a remarkable genotype–phenotype correlation of skin and hair findings in prepubescent males with XLHED. © 2014 Wiley Periodicals, Inc.
Patrick Calvas - One of the best experts on this subject based on the ideXlab platform.
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x linked and autosomal recessive Hypohidrotic Ectodermal Dysplasia genotypic dental phenotypic findings
Clinical Genetics, 2010Co-Authors: Francois Clauss, Nicolas Chassaing, Marieclaire Vincent, Patrick Calvas, A Smahi, M Molla, Herve Lesot, Yves Alembik, S Hadjrabia, C BodemerAbstract:Hypohidrotic Ectodermal Dysplasia (HED) is characterized by abnormal development of Ectodermal structures and its molecular etiology corresponds to mutations of EDA-EDAR genes. The aim of this study was first to investigate the genotype and dental phenotype associated with HED and second, to explore possible correlations between dental features and molecular defects. A total of 27 patients from 24 unrelated families exhibiting clinical signs of HED (22 XLHED males, 5 autosomal recessive forms) were retrospectively included. In the sample, 25 different mutations on EDA and EDAR genes were detected; 10 were not previously described. EDA and EDAR mutations corresponded respectively to 80.0% and 20.0% of the mutations. The dental phenotype analysis revealed a mean number of primary and permanent missing teeth ranging respectively from 14.5 (4-20) to 22.5 (10-28); the majority of the patients exhibited dysmorphic teeth. Overall, no differential expression in the degree of oligodontia according to either the mutated gene, the mutated functional sub-domains, or the mutation type, could be observed. Nevertheless, the furin group exhibited severe phenotypes unobserved in the TNF group. Significant differences in the number of some primary missing teeth (incisor and canine) related to EDA-EDAR genes defects were detected for the first time between XLHED and autosomal recessive HED, suggesting differential local effects of EDA-EDAR genes during odontogenesis. The present genotypic-phenotypic findings may add to the knowledge of the consequences of the molecular dysfunction of EDA-NF-kB in odontogenesis, and could be helpful in genetic counseling to distinguish autosomal forms from other HED syndromes.
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mutations in edaradd account for a small proportion of Hypohidrotic Ectodermal Dysplasia cases
British Journal of Dermatology, 2010Co-Authors: Nicolas Chassaing, Celine Cluzeau, Elodie Bal, Philippe Guigue, Marieclaire Vincent, Geraldine Viot, D Ginisty, Arnold Munnich, A Smahi, Patrick CalvasAbstract:Summary Background Hypohidrotic Ectodermal Dysplasia (HED) is characterized by abnormal development of the eccrine sweat glands, hair and teeth. The X-linked form of the disease, caused by mutations in the EDA gene, represents the majority of HED cases. Autosomal dominant and recessive forms occasionally occur and result from mutations in at least two other genes: EDAR and EDARADD. EDARADD interacts with the TAB2/TRAF6/TAK1 complex, which is necessary for NF-κB activation by EDAR. Objectives To determine frequency of EDARADD, TRAF6, TAB2 and TAK1 mutations in HED. Materials and methods We have screened 28 familial or sporadic HED cases with no mutations in the EDA and EDAR genes for EDARADD, TRAF6, TAB2 and TAK1 mutations. Results We identified one EDARADD 6-bp homozygous in-frame deletion (c.402-407del, p.Thr135-Val136del) in a patient born to consanguineous parents. Functional studies showed that the p.Thr135-Val136del impaired the EDAR–EDARADD interaction and then severely inhibited NF-κB activity. In the remaining 27 patients, we failed to find causative mutations in EDARADD, or in TRAF6, TAB2 or TAK1. Conclusions Our study demonstrates that EDARADD mutations are not a frequent cause of HED, while mutations in TRAF6, TAB2 and TAK1 may not be implicated in this disease.
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mutational spectrum of the ed1 gene in x linked Hypohidrotic Ectodermal Dysplasia
European Journal of Human Genetics, 2001Co-Authors: Marie Vincent, Valerie Biancalana, Daniele Ginisty, Jean L Mandel, Patrick CalvasAbstract:X-linked Hypohidrotic Ectodermal Dysplasia (XLHED) is the most common form of the Ectodermal Dysplasias characterised by an abnormal development of eccrine sweat glands, hair and teeth. The ED1 gene responsible for the disorder undergoes extensive alternative splicing and to date few studies have concerned the full length transcript. We screened 52 unrelated families or sporadic cases for mutation in the full coding sequence of this gene. SSCA analysis or direct sequencing allowed identification of mutations in 34 families: one initiation defect, twenty-two missenses, two nonsense, eight insertions or deletions, and a large deletion encompassing all the ED1 gene. Fourteen of these mutations have not been previously described, including five missenses. One third of identified mutations were localised in codons 155 and 156, affecting CpG dinucleotides and nine of them correspond to the R156H missense. Hypothesis of a founder effect has been ruled out by haplotype analysis of flanking microsatellites. These recurrent mutations indicate the functional importance of the positively charged domain of the protein. Including our data, there are now 56 different mutations reported in 85 independent patients, that we have tabulated. Review of clinical features in the present series of affected males and female carriers showed no obvious correlation between the type of mutations, the phenotype and its severity. The X-chromosome pattern of inactivation in leucocytes showed little correlation with expressivity of the disease in female carriers. Finally this study is useful for functional studies of the protein and to define a diagnostic strategy for mutation screening of the ED1 gene.
